There is now unequivocal evidence that the immune system is equipped to detect and react to cellular stress signals generated by normal cells undergoing neoplastic transformation and the cancers that arise from them. Although the frequency and magnitude of such responses vary considerably between individuals, both pre-clinical models and clinical studies have established that the cancer phenotype, its biological behavior, and clinical prognosis are profoundly influenced by the character of the host immune response. Cellular and humoral immunity recognize a wide range of antigenic targets on cancer cells, many of which are being pursued as candidates for immunotherapy. Yet cancers are comprised of heterogeneous cell populations, varying in patterns of gene expression and in the resulting distribution of target antigens. These phenotypic differences are superimposed upon functional differences in the capacity of subsets of cancer cells to self-renew and propagate the malignancy. Consequently, there is little evidence to guide which of these antigens when targeted are most likely to confer clinical benefit. We seek to address this limitation using an unbiased antigen identification strategy in two clinical settings where there is measurable evidence of an immune mediated clinical effect; in vaccine associated remission induction in 1) chronic myelogenous leukemia (CML) and 2) acute myelogenous leukemia (AML). Antigens identified in these screenings will be prioritized based on the following criteria: 1) correlation of immune recognition with clinical response, 2) expression by leukemic stem cells (LSCs), 3) detection of both antibody and T cell responses, and 4) the biological role played by the gene in pathways of leukemogenesis. Prioritized antigens will be validated based on the impact of their targeting on in vivo engraftment of leukemia versus normal hematopoiesis. These findings will provide significant insight into the essential components of cancer stem cells, help to establish immune laboratory correlates predictive of clinical responses, and guide the selection of antigenic targets for defined-antigen vaccine or adoptive T cell therapies for leukemia. PUBLIC HEALTH RELEVANCE: Immune responses to cancer occur in some patients and are associated with a more favorable outcome. Methods now exist to identify the molecules on cancer cells recognized by antibodies and T cells, however it is not known which of these many targets are present on the cells most responsible for cancer growth. The identification of immune targets in leukemia will teach us what components of the cancer are most essential to eliminate, and provide new tools to develop and evaluate more effective immune-based therapies.